Cytogenetic and molecular studies of trisomy 13.
Chromosome heteromorphisms, restriction fragment length polymorphisms, or both were used to study the parental origin of 33 cases of simple trisomy 13 and eight cases of translocation trisomy 13. The most common origin for the simple trisomies was non-disjunction at maternal meiosis I, while for the translocations an equal number of paternally and maternally derived cases was observed. In seven of the simple trisomies, information was obtained from both the cytogenetic and molecular markers, making it possible to study recombination between the two non-disjoined chromosomes. Five of the seven cases involved errors at meiosis I, with crossing over being detected in two of three cases of maternal origin and in one of two cases of paternal origin. This indicates that absence of recombination because of pairing failure is unlikely to be of major importance in the genesis of trisomy 13.


Timing of wound closure in open fractures based on cultures obtained after debridement.
The timing of wound closure in open fractures has remained an inexact science. Numerous recommendations have been made for the management of these injuries regarding the optimal time to perform competent wound closure, with all advice based on subjective parameters. The purpose of this study was to determine the utility of a prospective protocol with use of wound cultures obtained after irrigation and debridement as a guide to the timing of wound closure following an open fracture of an extremity. Four hundred and twenty-two open fractures had emergency irrigation and debridement, fracture stabilization, and open wound management. Wound cultures were obtained for aerobic and anaerobic analysis following debridement. At forty-eight hours after debridement, patients were again returned to surgery. If the initial culture results were positive, a repeat irrigation and debridement was carried out, and additional cultures were obtained after debridement. This procedure was repeated, and the wound was not closed until negative culture results were achieved. Of the 422 open fractures, 346 were available for long-term follow-up. The overall deep infection rate was 4.3%. Gustilo Type-II fractures had a deep infection rate of 4%, and Type-III fractures had an infection rate of 5.7%. Type-III fractures demonstrated differences among the fracture patterns within this type, as infection developed in 1.8% of Type-IIIA injuries, 10.6% of Type-IIIB fractures, and 20% of Type-IIIC fractures. Fractures requiring multiple debridement procedures and those in patients with diabetes or an increased body mass index demonstrated higher rates of infection. With the numbers studied, fractures in which the wound was closed in the presence of positive cultures (a protocol breach) did not have a significantly increased risk of deep infection (p = 0.0501). The use of this standardized protocol was shown to achieve a very low rate of deep infection compared with historical controls. An increased number of irrigation and debridement procedures are required to achieve this improved outcome. Therapeutic Level IV. See Instructions to Authors for a complete description of levels of evidence.


Determination of Interfacial Amorphicity in Functional Powders.
The nature of the surfaces of particles of pharmaceutical ingredients, food powders, and polymers is a determining factor for their performance in for example tableting, powder handling, or mixing. Changes on the surface structure of the material will impact the flow properties, dissolution rate, and tabletability of the powder blend. For crystalline materials, surface amorphization is a phenomenon which is known to impact performance. Since it is important to measure and control the level of amorphicity, several characterization techniques are available to determine the bulk amorphous content of a processed material. The possibility of characterizing the degree of amorphicity at the surface, for example by studying the mechanical properties of the particles' surface at the nanoscale, is currently only offered by atomic force microscopy (AFM). The AFM PeakForce QNM technique has been used to measure the variation in energy dissipation (eV) at the surface of the particles which sheds light on the mechanical changes occurring as a result of amorphization or recrystallization events. Two novel approaches for the characterization of amorphicity are presented here. First, since particles are heterogeneous, we present a methodology to present the results of extensive QNM analysis of multiple particles in a coherent and easily interpreted manner, by studying cumulative distributions of dissipation data with respect to a threshold value which can be used to distinguish the crystalline and amorphous states. To exemplify the approach, which is generally applicable to any material, reference materials of purely crystalline α-lactose monohydrate and completely amorphous spray dried lactose particles were compared to a partially amorphized α-lactose monohydrate sample. Dissipation data are compared to evaluations of the lactose samples with conventional AFM and SEM showing significant topographical differences. Finally, the recrystallization of the surface amorphous regions in response to humidity was followed by studying the dissipation response of a well-defined surface region over time, which confirms both that dissipation measurement is a useful measure of surface amorphicity and that significant recrystallization occurs at the surface in response to humidity.


Genotypic diversity effects on biomass production in native perennial bioenergy cropping systems.
The perennial grass species that are being developed as biomass feedstock crops harbor extensive genotypic diversity, but the effects of this diversity on biomass production are not well understood. We investigated the effects of genotypic diversity in switchgrass (Panicum virgatum) and big bluestem (Andropogon gerardii) on perennial biomass cropping systems in two experiments conducted over 2008-2014 at a 5.4-ha fertile field site in northeastern Illinois, USA. We varied levels of switchgrass and big bluestem genotypic diversity using various local and nonlocal cultivars - under low or high species diversity, with or without nitrogen inputs - and quantified establishment, biomass yield, and biomass composition. In one experiment ('agronomic trial'), we compared three switchgrass cultivars in monoculture to a switchgrass cultivar mixture and three different species mixtures, with or without N fertilization. In another experiment ('diversity gradient'), we varied diversity levels in switchgrass and big bluestem (1, 2, 4, or 6 cultivars per plot), with one or two species per plot. In both experiments, cultivar mixtures produced yields equivalent to or greater than the best cultivars. In the agronomic trial, the three switchgrass mixture showed the highest production overall, though not significantly different than best cultivar monoculture. In the diversity gradient, genotypic mixtures had one-third higher biomass production than the average monoculture, and none of the monocultures were significantly higher yielding than the average mixture. Year-to-year variation in yields was lowest in the three-cultivar switchgrass mixtures and Cave-In-Rock (the southern Illinois cultivar) and also reduced in the mixture of switchgrass and big bluestem relative to the species monocultures. The effects of genotypic diversity on biomass composition were modest relative to the differences among species and genotypes. Our findings suggest that local genotypes can be included in biomass cropping systems without compromising yields and that genotypic mixtures could help provide high, stable yields of high-quality biomass feedstocks.


Desaturation of the Sphingofungin Polyketide Tail Results in Increased Serine Palmitoyltransferase Inhibition.
Serine palmitoyltransferase catalyzes the first step of the sphingolipid biosynthesis. Recently, sphingolipid homeostasis has been connected to several human diseases, making serine palmitoyltransferases an interesting therapeutic target. Known and efficient serine palmitoyltransferase-inhibitors are sphingofungins, a group of natural products isolated from fungi. To further characterize newly isolated sphingofungins, we designed an easy to use colorimetric serine palmitoyltransferase activity assay using FadD, which can be performed in 96-well plates. Because sphingofungins exert antifungal activitiy as well, we compared the in vitro assay results with an in vivo growth assay using Saccharomyces cerevisiae. The reported experiments showed differences among the assayed sphingofungins, highlighting an increase of activity based on the saturation levels of the polyketide tail. IMPORTANCE Targeting the cellular sphingolipid metabolism is often discussed as a potential approach to treat associated human diseases such as cancer and Alzheimer's disease. Alternatively, it is also a possible target for the development of antifungal compounds, which are direly needed. A central role is played by the serine palmitoyltransferase, which catalyzes the initial and rate limiting step of sphingolipid de novo synthesis and, as such, the development of inhibitory compounds for this enzyme is of interest. Our work here established an alternative approach for determining the activity of serine palmitoyltransferase adding another tool for the validation of its inhibition. We also determined the effect of different modifications to sphingofungins on their inhibitory activity against serine palmitoyltransferase, revealing important differences on said activity against enzymes of bacterial and fungal origin.


Match probability calculations for multi-locus DNA profiles.
The paper considers aspects of the match probability calculation for multi-locus DNA profiles and a related calculation which aims to assess the probability that a pair of profiles is concordant for the presence and absence of bands. It is suggested that levels of allelism and linkage for multi-locus profiles may be higher than reported in previous studies, and that comparison of bandsharing values between different studies is problematic. Our view is that the independence assumptions which underpin the calculations have not been established. The effect of ignoring (local) heterogeneities in band frequencies may be non-conservative. Concerns thus raised about the match probability calculation could be important in practical casework. The speculative nature of some aspects of the concordance probability calculation would seem to render it inappropriate for use in court.


Occupational Blast Wave Exposure During Multiday 0.50 Caliber Rifle Course.
Research on blast overpressure (BOP) experienced by military personnel in operations like breaching, identifies transient, measurable effects on operator readiness. Specifically, blast seems to be associated with suppressed response speed and cognitive function. This work evaluates 50 caliber weapon systems to ascertain BOP effects from the weapon usage. Marksmen were a collection of professionals who use 0.50 caliber weapon systems as part of their daily activities, and the environment measured was during a training course. The 20 human subjects were equipped with B3 blast gauges and occupational BOP exposure monitored over the course of 3 day training period with measurements taken from 500+ shots. We noted a considerable variation in total cumulative peak pressure (50-350 psi) and impulse (25-180 psi·ms) values. The frequency analysis (number of shots fired by the trainee) revealed that the number of exposures per day varied between 4 and 27 per day (peak at 7: 14.3% of the data), and 2 to 17 per hour (peak at 8: 18% of the data). The cumulative number of exposures was 24-50 per trainee. The neurocognitive performance was evaluated using Defense Automated Neurobehavioral Assessment (DANA) Rapid: Simple Reaction Time (SRT), Procedural Reaction Time (PRT) and Go/No-Go (GNG). The results recorded before the training were a baseline for each training day and compared with the results recorded after and at the end of the day. Only PRT and GNG tests revealed a cumulative increase in proportion of subjects with slowed reaction times over the progression of course with concomitant dispersion increase at the end of the day. Noticeably, on average 2/3rd of the trainees performed faster, while 1/3rd of trainees performed these tasks slower, but there was no correlation with the cumulative pressure dosage. The fatigue appears as an aggravating factor affecting the neurocognitive performance, and a more sophisticated evaluation regimen is necessary to discern potential neurological effects. Additional investigation is needed to understand the increasing dispersion of results between subjects and future works should be mindful of such continued trends. Future work should seek to determine the recovery period and longitudinal effects of heavy usage of these weapon systems.


Human cysticercosis of the breast mimicking breast cancer: a report of a case from Ile-Ife, Nigeria. .
Human cystericosis is the infection caused by the larvae of pork tapeworm Taeniasolium. The infection commonly affects the muscle, the central nervous system and subcutaneous tissues. The involvement of the breast is unusual. To present a 54 years old postmenopausal woman, a petty trader and a Jehovah witness who presented with a painless lump in the right breast which was increasing in size. The mass was clinically diagnosed by the Surgeon who examined her as a case of right breast cancer and an excisional biopsy was done. A review of the case note, autopsy findings including gross and microscopic examinations and literature was done. A histopathological appraisal of biopsy revealed the presence of the typical cysticercus larva and a definitive diagnosis of right breast Cystericosis was made. The diagnosis of cysticercosis in unusual sites such as breast may be clinically difficult and this supports why all biopsies must be sent to the pathologists for definitive diagnosis. Human cystericosis of the breast is rare, nevertheless, this should be considered as a differential diagnosis for amass in the breast particularly in the tropics and developing countries. To the best of our knowledge, this is the first case from our centre.


NTP Toxicology and Carcinogenesis Studies of 4-Hexylresorcinol (CAS No. 136-77-6) in F344/N Rats and B6C3F1 Mice (Gavage Studies).
4-Hexylresorcinol, which is used as an anthelmintic and antiseptic, was nominated by the National Cancer Institute for study. Toxicology and carcinogenesis studies were conducted by administering 4-hexylresorcinol (greater than 99% pure) in corn oil by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 16 days, 13 weeks, or 2 years. Sixteen-Day and Thirteen-Week Studies: In the 16-day studies, groups of five rats and five mice of each sex were administered 0, 31.3, 62.5, 125, 250, or 500 mg/kg 4-hexylresorcinol. Survival was not affected. Decreased body weights were seen in male rats that received 250 or 500 mg/kg 4-hexylresorcinol. No other effects were observed. In the 13-week studies, groups of 10 rats and 10 mice of each sex were administered 0, 62.5, 125, 250, 500, or 1,000 mg/kg of the chemical, 5 days per week. All rats and male mice and 9/10 female mice that received 1,000 mg/kg died before the end of the studies. Final mean body weights of male rats that received 250 or 500 mg/kg were 22% or 38% lower than that of the vehicle controls; final mean body weights of female rats that received 250 or 500 mg/kg were 16% or 9% lower. No compound-related gross or microscopic pathologic effects were observed in rats. No body weight effects were observed for mice. Mild to moderate nephropathy was dose related in male and female mice. Based on these results, 2-year toxicology and carcinogenesis studies of 4-hexylresorcinol were conducted by administering 0, 62.5, or 125 mg/kg to groups of 50 F344/N rats and 50 B6C3F1 mice of each sex, 5 days per week. Body Weight and Survival in the Two-Year Studies: Mean body weights of high dose male rats were 7%-11% lower than those of the vehicle controls throughout the study. Mean body weights of low dose male and dosed female rats were similar to those of the vehicle controls. The body weights of dosed male and dosed female mice were comparable to those of vehicle controls except during the last 16 weeks of the studies, when body weights were 6%-16% lower in the dosed groups. No significant differences in survival were observed between any groups of rats or mice of either sex (male rats: vehicle control, 30/50; low dose, 29/50; high dose, 33/50; female rats: 28/50; 32/50; 30/50; male mice: 36/50; 26/50; 30/50; female mice: 35/50; 32/50; 35/50). Nonneoplastic and Neoplastic Lesions in the Two-Year Studies: Two astrocytomas and an oligodendroglioma were observed in high dose male rats, a glioma was observed in one low dose male rat, and an oligodendroglioma was observed in one vehicle control male rat. These neoplasms were not considered to be related to 4-hexylresorcinol administration. Focal medullary hyperplasia of the adrenal gland was observed at increased incidences in dosed male mice (5/50; 16/50; 10/49). Pheochromocytomas in male mice occurred with a marginal upward trend (1/50; 2/50; 5/49). Historically, these neoplasms are observed in about 1% of corn oil vehicle control B6C3F1 male mice. The incidences of neoplasms of the harderian gland in male mice were slightly increased over those in the vehicle controls (adenomas or carcinomas, combined: 0/50; 4/50; 3/50). Decreases were observed in the incidences of mononuclear cell leukemia in dosed male (12/49; 7/50; 1/50) and female (16/50; 3/50; 2/50) rats, hepatocellular adenomas or carcinomas (combined) in dosed male mice (21/50; 9/50; 9/50), and circulatory system tumors in male (10/50; 4/50; 2/50) and female (6/50; 2/49; 0/50) mice. These decreased incidences of tumors in rats and mice are considered to be possibly related to 4-hexylresorcinol administration. The incidences and severity of nephropathy (male: 39/50; 43/50; 47/50; female: 7/50; 40/49; 47/50) and incidences of osteosclerosis (male: 5/50; 5/50; 15/50; female: 21/50; 25/49; 40/50) were increased in both dosed male and female mice and are considered to be related to chemical exposure. Genetic Toxicology: 4-Hexylresorcinol was not mutagenic for Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 with or without S9 metabolic activation. 4-Hexylre, TA1535, or TA1537 with or without S9 metabolic activation. 4-Hexylresorcinol induced forward mutations at the TK locus in mouse L5178Y cells in the presence of S9; no response was observed in the absence of metabolic activation. In cytogenetic assays with cultured Chinese hamster ovary (CHO) cells, 4-hexylresorcinol caused an increase in the frequency of sister chromatid exchanges (SCEs) in the absence of metabolic activation; no induction of SCEs was observed in the presence of S9. Chromosomal aberrations were not induced in CHO cells with or without metabolic activation. Data Audit: The data, documents, and pathology materials from the 2-year studies of 4-hexylresorcinol were audited at the NTP Archives. The audit findings show that the conduct of the studies is documented appropriately and support the data and results given in this Technical Report. Conclusions: Under the conditions of these 2-year gavage studies, there was no evidence of carcinogenic activity of 4-hexylresorcinol for male or female F344/N rats given doses of 62.5 or 125 mg/kg. There was equivocal evidence of carcinogenic activity of 4-hexylresorcinol for male B6C3F1 mice, as shown by marginally increased incidences of pheochromocytomas (and hyperplasia) of the adrenal medulla and of harderian gland neoplasms. There was no evidence of carcinogenic activity for female B6C3F1 mice given doses of 62.5 or 125 mg/kg 4-hexylresorcinol. Decreased incidences of three tumors types were considered related to 4-hexylresorcinol administration: mononuclear cell leukemia in male and female rats, hepatocellular neoplasms in male mice, and circulatory system tumors in male and female mice. Synonyms: 4-hexyl-1,3-benzenediol; 4-hexyl-1,3-dihydroxybenzene


Thrombospondin-1 induces apoptosis in primary leukemia and cell lines mediated by CD36 and Caspase-3.
Thrombospondin-1 (TSP-1) is a naturally occurring anti-angiogenic compound that induces apoptosis of endothelial and cancer cells via its receptor CD36. The objectives of our study were to investigate the in vitro effects of TSP-1 on the apoptosis of primary human leukemia cells as well as leukemia cell lines and the possible mechanism involving CD36. Our results demonstrated that TSP-1 induced apoptosis in CD36 positive cell lines CHRF-288-11, Meg-01 and HL-60, but not CD36 negative K562, at a dose-dependent manner as demonstrated by DNA ladder formation, Annexin V and propidium iodide (PI) stainings. The addition of anti-CD36 antibody FA6-152 or thrombopoietin (TPO) significantly nullified the effects of TSP-1. TSP-1-mediated apoptosis was consistently associated with the up-regulation of active Caspase-3. Responses of 2 CD36 positive primary AML samples to TSP-1 and FA6-152 were similar with those of leukemia cell lines. TSP-1 significantly induced apoptosis in B-ALL but the counter-effects of FA6-152 were less apparent. CD36 negative AML cells appeared less susceptible to TSP-1 and FA6-152. Our data provided strong evidence that TSP-1 exerted direct apoptotic effects on leukemia cells and could be developed as an adjunct to conventional therapy, particularly for leukemia cells that express CD36 or other TSP-1 receptors.


Immunization of mice with Plasmodium TCTP delays establishment of Plasmodium infection.
Translationally controlled tumour protein (TCTP) may play an important role in the establishment or maintenance of parasitemia in a malarial infection. In this study, the potential of TCTP as a malaria vaccine was investigated in two trials. In the initial vaccine trial, Plasmodium falciparum TCTP (PfTCTP) was expressed in Saccharomyces cerevisiae and used to immunize BALB/c mice. Following challenge with Plasmodium yoelii YM, parasitemia was significantly reduced during the early stages of infection. In the second vaccine trial, the TCTP from P. yoelii and P. berghei was expressed in Escherichia coli and used in several mouse malaria models. A significant reduction in parasitemia in the early stages of infection was observed in BALB/c mice challenged with P. yoelii YM. A significantly reduced parasitemia at each day leading up to a delayed and reduced peak parasitemia was also observed in BALB/c mice challenged with the nonlethal Plasmodium chabaudi (P.c.) chabaudi AS. These results suggest that TCTP has an important role for parasite establishment and may be important for pathogenesis.


A rare location of sacral tuberculosis: A report of three cases.
Tuberculosis remains one of the most common infectious diseases in the world. Vertebral tuberculosis is the commonest form of bone and joint tuberculosis; however, isolated sacral tuberculosis is rare. This atypical presentation may lead to a delay in diagnosis and treatment. We report three cases of sacral tuberculosis diagnosed in young women, aged 30, 23, and 35 years old, respectively. Lombosciatic pain was the main symptom in all cases. All patients had a biological assessment, plain radiographs, and CT scan. However, magnetic resonance imaging was done in only two cases. All patients underwent surgical sacral biopsy, and the diagnosis of tuberculosis was confirmed by histology in all cases. The evolution was satisfactory with the adjunction of antituberculous chemotherapy in all cases. Spinal tuberculosis should be the first and foremost differential diagnosis in the presence of atypical clinical and radiological features of a sacral lesion, particularly in developing countries. Early diagnosis and treatment could prevent or minimize the neurological morbidity in such cases.


Antimicrobial activity of coriander oil and its effectiveness as food preservative.
ABTRACT Foodborne illness represents a major economic burden worldwide and a serious public health threat, with around 48 million people affected and 3,000 death each year only in the USA. One of the possible strategies to reduce foodborne infections is the development of effective preservation strategies capable of eradicating microbial contamination of foods. Over the last years, new challenges for the food industry have arisen such as the increase of antimicrobial resistance of foodborne pathogens to common preservatives and consumers demand for naturally based products. In order to overcome this, new approaches using natural or bio-based products as food preservatives need to be investigated. Coriander (Coriandrum sativum L.) is a well-known herb widely used as spice, or in folk medicine, and in the pharmacy and food industries. Coriander seed oil is the world's second most relevant essential oil, exhibiting antimicrobial activity against Gram-positive and Gram-negative bacteria, some yeasts, dermatophytes and filamentous fungi. This review highlights coriander oil antimicrobial activity and possible mechanisms of action in microbial cells and discusses the ability of coriander oil usage as a food preservative, pointing out possible paths for the successful evolution for these strategies towards a successful development of a food preservation strategy using coriander oil.


The role of M2 muscarinic receptor subtypes mediating contraction of the circular and longitudinal smooth muscle of the pig proximal urethra.
We investigated the characterization of muscarinic receptor subtypes in the female pig urethra. The affinities of muscarinic antagonists against carbachol responses were calculated in normal and cyclic adenosine monophosphate (cAMP) elevated tissues (contraction with KCl and relaxation with isoprenaline) using longitudinal and transverse strips of urethra. In displacement experiments with 1-quinuclidinyl [phenyl-4-3H] benzilate inhibitory constant (pKi) values of 4-diphenylacetoxyl-N-methyl-piperidine methiodide (DAMP) M3 selective antagonist) and methoctramine (M2 antagonist) indicated the presence of the M2 receptor. In functional studies contraction responses to carbachol were greater in longitudinal than in circular muscle. After cAMP elevation the contraction response increased in circular muscles to the level close to that of longitudinal muscles but did not change significantly in cAMP elevated longitudinal muscle. On normal circular tissues 4-DAMP had high mean affinity (mean apparent pKB value 9.3) but with a Schild slope of less than unity (0.76). Methoctramine competitively antagonized carbachol responses (mean affinity [pA2] value 6.9). On normal longitudinal tissues 4-DAMP and methoctramine competitively antagonized carbachol responses (mean pA2 9.0 and 6.2, respectively). After cAMP elevation in circular tissues mean pA2 values for 4-DAMP (8.7) were significantly lower (p = 0.0015), and those for methoctramine (7.3) were significantly higher (p = 0.0193) than in normal tissues. In longitudinal tissues the mean pA2 value for methoctramine (6.9) was significantly greater than in normal tissues (p <0.0001) but the value for 4-DAMP (8.8) did not alter. Pig urethra appears to have predominantly M2 muscarinic receptors. Contraction of the normal urethra appears to be predominantly mediated by M2 and M3 receptors in circular muscle but by M3 receptors in longitudinal muscle. After cAMP elevation a contribution to contraction of M2 receptors appeared to be demonstrated in the 2 tissues but the involvement of M2 receptors appeared greater in circular muscle.


Hyperbaric oxygenation combined with nifedipine treatment for recent-onset retinal artery occlusion.
We describe the results of early hyperbaric oxygenation combined with nifedipine treatment for central retinal artery occlusion, and explain the results pathophysiologically. We report four cases in which hyperbaric oxygenation therapy was applied in combination with nifedipine, eyeball massage, and glycerol for the treatment of central retinal artery occlusion. In two of the cases in which therapy was started less than 100 minutes after the acute onset of visual loss and one case in which therapy was started during the course of central arterial occlusion, considerable improvement in visual acuity was observed, while in the fourth case in which therapy was started six hours after the acute onset of visual loss, no improvement appeared. We conclude from these results that hyperbaric oxygenation therapy has a beneficial effect on the final visual outcome of central retinal artery occlusion, provided it is applied early enough. Further investigation is needed to fully define the nature and terms of this beneficial effect.


Short-term responses of leaf growth rate to water deficit scale up to whole-plant and crop levels: an integrated modelling approach in maize.
Physiological and genetic studies of leaf growth often focus on short-term responses, leaving a gap to whole-plant models that predict biomass accumulation, transpiration and yield at crop scale. To bridge this gap, we developed a model that combines an existing model of leaf 6 expansion in response to short-term environmental variations with a model coordinating the development of all leaves of a plant. The latter was based on: (1) rates of leaf initiation, appearance and end of elongation measured in field experiments; and (2) the hypothesis of an independence of the growth between leaves. The resulting whole-plant leaf model was integrated into the generic crop model APSIM which provided dynamic feedback of environmental conditions to the leaf model and allowed simulation of crop growth at canopy level. The model was tested in 12 field situations with contrasting temperature, evaporative demand and soil water status. In observed and simulated data, high evaporative demand reduced leaf area at the whole-plant level, and short water deficits affected only leaves developing during the stress, either visible or still hidden in the whorl. The model adequately simulated whole-plant profiles of leaf area with a single set of parameters that applied to the same hybrid in all experiments. It was also suitable to predict biomass accumulation and yield of a similar hybrid grown in different conditions. This model extends to field conditions existing knowledge of the environmental controls of leaf elongation, and can be used to simulate how their genetic controls flow through to yield.


Impact of High Volume Energy Drink Consumption on Electrocardiographic and Blood Pressure Parameters: A Randomized Trial.
Background Energy drinks have been linked to an increase in emergency room visits and deaths. We aim to determine the impact of energy drinks on electrocardiographic and hemodynamic parameters in young healthy volunteers. Methods and Results A randomized, double-masked, placebo-controlled, crossover study was conducted in healthy volunteers. Participants consumed 32 oz of either energy drink A, energy drink B, or placebo within 60 minutes on 3 study days with a 6-day washout period in between. The primary end point of QT c interval and secondary end points of QT interval, PR interval, QRS duration, heart rate, and brachial and central blood pressures were measured at baseline, and every 30 minutes for 240 minutes. A repeated-measures 2-way analysis of variance was performed with the main effects of intervention, time, and an interaction of intervention and time. Thirty-four participants were included (age 22.1±3.0 years). The interaction term of intervention and time was statistically significant for Bazett's corrected QT interval, Fridericia's corrected QT interval, QT , PR , QRS duration, heart rate, systolic blood pressure, diastolic blood pressure, central systolic blood pressure, and central diastolic blood pressure (all P<0.001). The maximum change from baseline in Bazett's corrected QT interval for drinks A, B, and placebo were +17.9±13.9, +19.6±15.8, and +11.9±11.1 ms, respectively ( P=0.005 for ANOVA ) ( P=0.04 and <0.01, respectively compared with placebo). Peripheral and central systolic and diastolic blood pressure were statistically significantly different compared with placebo (all P<0.001). Conclusion Energy drinks significantly prolong the QT c interval and raise blood pressure. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT03196908.


Assessment of liver fibrosis in co-infected patients.
The evaluation of liver injury in HIV patients co-infected with HBV and HCV should follow the same principles as the evaluation of any patient with chronic liver disease. The initial clinical evaluation should include documentation of risk factors for progressive disease. HIV history is important particularly with respect to a past history of significant or prolonged immunosuppression as this has been clinically correlated with more advanced liver disease. Liver transaminases are an important predictor of disease severity and progression in HIV patients. Liver biopsy has remained the 'gold standard' for the grading of inflammation and staging of disease. We would still recommend liver biopsy in HIV patients particularly those with HCV because recent community-based studies in the HAART era have suggested slower rates of progression for HIV/HCV than studies from tertiary care centres and older cohorts. Since, liver biopsy is invasive and expensive, non-invasive techniques including serological tests and novel imaging techniques have evolved to stage liver fibrosis. A novel technique for measuring hepatic elasticity has recently been validated alone and in combination with serum markers for HCV mono-infection. Future trends for staging liver disease must not only focus on cross sectional diagnosis but on utilizing novel techniques to stratify risk for disease progression over time.


Variation in lung function and alterations in cardiac structure and function-Analysis of the UK Biobank cardiovascular magnetic resonance imaging substudy.
Reduced lung function is common and associated with increased cardiovascular morbidity and mortality, even in asymptomatic individuals without diagnosed respiratory disease. Previous studies have identified relationships between lung function and cardiovascular structure in individuals with pulmonary disease, but the relationships in those free from diagnosed cardiorespiratory disease have not been fully explored. UK Biobank is a prospective cohort study of community participants in the United Kingdom. Individuals self-reported demographics and co-morbidities, and a subset underwent cardiovascular magnetic resonance (CMR) imaging and spirometry. CMR images were analysed to derive ventricular volumes and mass. The relationships between CMR-derived measures and spirometry and age were modelled with multivariable linear regression, taking account of the effects of possible confounders. Data were available for 4,975 individuals, and after exclusion of those with pre-existing cardiorespiratory disease and unacceptable spirometry, 1,406 were included in the analyses. In fully-adjusted multivariable linear models lower FEV1 and FVC were associated with smaller left ventricular end-diastolic (-5.21ml per standard deviation (SD) change in FEV1, -5.69ml per SD change in FVC), end-systolic (-2.34ml, -2.56ml) and stroke volumes (-2.85ml, -3.11ml); right ventricular end-diastolic (-5.62ml, -5.84ml), end-systolic (-2.47ml, -2.46ml) and stroke volumes (-3.13ml, -3.36ml); and with lower left ventricular mass (-2.29g, -2.46g). Changes of comparable magnitude and direction were observed per decade increase in age. This study shows that reduced FEV1 and FVC are associated with smaller ventricular volumes and reduced ventricular mass. The changes seen per standard deviation change in FEV1 and FVC are comparable to one decade of ageing.


Episodic memories of relationship quality, procedural knowledge of attachment scripts, and the experience of daughters caring for a parent with dementia.
A caregiver's attachment history with their parents may affect the thoughts, feelings, and behavior they now have as they care for a parent with dementia. Participants were 77 daughters of a parent with dementia. The nature of participant conscious episodic memories of their parental figures and unconscious procedural knowledge of caregiving processes (secure base script knowledge) were identified as two aspects of the caregiver's relationship history that may impact their involvement in care, relationship conflict, critical attitudes, and strain. Our findings indicated that the nature of episodic memories of the caregiver relationship history with parental figures were significantly associated with stress and criticism of their parent. Greater unconscious procedural knowledge of the secure base script was associated with caregiver report of less conflict and less involvement in the caregiving tasks. Potential clinical implications of this pattern are also discussed.


Wound Healing Activity of Silibinin in Mice.
Silibinin is a semi-purified fraction of silymarin contained in milk thistle (Silybum marianum Asteraceae). Primarily known for its hepatoprotective actions, silymarin may also stimulate epithelialization and reduce inflammation in excision wound. Previous studies show antioxidant, anti-inflammatory, and antimicrobial actions of silibinin. However, wound healing property of silibinin is not well studied. This study investigates wound healing activity of silibinin topical formulation. Wound healing activity of 0.2% silibinin gel was assessed by incision and excision wound models in mice. Animals were divided into gel base, silibinin gel, and Mega Heal gel® treated groups with six animals in each group. Wound contraction, wound tissue tensile strength, and hydroxyproline content were measured, and histopathological evaluation of wound tissue of all the above treatment groups was carried out. Application of 0.2% silibinin hydrogel for 8 days led to 56.3% wound contraction compared to 64.6% using standard Mega Heal gel with a subsequent increase in hydroxyproline content, which was significantly higher (P < 0.001) over control animals showing 33.2% contraction. After 14 days, percentage of contraction reached 96.1%, 97.6%, and 86.7%, respectively. Wound tissue tensile strength with silibinin (223.55 ± 3.82 g) and standard (241.38 ± 2.49 g) was significantly higher (P < 0.001) than control (174.06 ± 5.75 g). Histopathology of silibinin and standard gel treated wound tissue showed more fibroblasts, fewer macrophage infiltration, and well-formed collagen fibers. Here, we show potent wound healing activity of silibinin hydrogel formulation. 0.2% silibinin hydrogel showed potent wound healing activity in incision and excision wound models in mice. Abbreviations Used: ROS: Reactive oxygen species.


Modeling transitions in body composition: the approach to steady state for anthropometric measures and physiological functions in the Minnesota human starvation study.
This study evaluated whether the changes in several anthropometric and functional measures during caloric restriction combined with walking and treadmill exercise would fit a simple model of approach to steady state (a plateau) that can be solved using spreadsheet software (Microsoft Excel). We hypothesized that transitions in waist girth and several body compartments would fit a simple exponential model that approaches a stable steady-state. The model (an equation) was applied to outcomes reported in the Minnesota starvation experiment using Microsoft Excel's Solver function to derive rate parameters (k) and projected steady state values. However, data for most end-points were available only at t = 0, 12 and 24 weeks of caloric restriction. Therefore, we derived 2 new equations that enable model solutions to be calculated from 3 equally spaced data points. For the group of male subjects in the Minnesota study, body mass declined with a first order rate constant of about 0.079 wk-1. The fractional rate of loss of fat free mass, which includes components that remained almost constant during starvation, was 0.064 wk-1, compared to a rate of loss of fat mass of 0.103 wk-1. The rate of loss of abdominal fat, as exemplified by the change in the waist girth, was 0.213 wk-1.On average, 0.77 kg was lost per cm of waist girth. Other girths showed rates of loss between 0.085 and 0.131 wk-1. Resting energy expenditure (REE) declined at 0.131 wk-1. Changes in heart volume, hand strength, work capacity and N excretion showed rates of loss in the same range. The group of 32 subjects was close to steady state or had already reached steady state for the variables under consideration at the end of semi-starvation. When energy intake is changed to new, relatively constant levels, while physical activity is maintained, changes in several anthropometric and physiological measures can be modeled as an exponential approach to steady state using software that is widely available. The 3 point method for parameter estimation provides a criterion for testing whether change in a variable can be usefully modelled with exponential kinetics within the time range for which data are available.


Chimeric antigen receptor T Cells with dissociated signaling domains exhibit focused antitumor activity with reduced potential for toxicity in vivo.
Adoptive immunotherapy using T lymphocytes genetically modified to express a chimeric antigen receptor (CAR-T) holds considerable promise for the treatment of cancer. However, CAR-based therapies may involve on-target toxicity against normal tissues expressing low amounts of the targeted tumor-associated antigen (TAA). To specify T cells for robust effector function that is selective for tumor but not normal tissue, we developed a trans-signaling CAR strategy, whereby T-cell activation signal 1 (CD3z) is physically dissociated from costimulatory signal 2 (CD28) in two CARs of differing antigen specificity: mesothelin and a-folate receptor (FRa). Human T cells were genetically modified to coexpress signal 1 (anti-Meso scFv-CD3z) and signal 2 (anti-FRa scFv-CD28) CARs in trans. Trans-signaling CAR-T cells showed weak cytokine secretion against target cells expressing only one TAA in vitro, similar to first-generation CAR-T cells bearing CD3z only, but showed enhanced cytokine secretion upon encountering natural or engineered tumor cells coexpressing both antigens, equivalent to that of second-generation CAR-T cells with dual signaling in cis. CAR-T cells with dual specificity also showed potent anticancer activity and persistence in vivo, which was superior to first-generation CAR-T cells and equivalent to second-generation CARs. Importantly, second-generation CAR-T cells exhibited potent activity against cells expressing mesothelin alone, recapitulating normal tissue, whereas trans-signaling CAR-T cells did not. Thus, a dual specificity, trans-signaling CAR approach can potentiate the therapeutic efficacy of CAR-T cells against cancer while minimizing parallel reactivity against normal tissues bearing single antigen.


Impact and Cost-Effectiveness of Point-Of-Care CD4 Testing on the HIV Epidemic in South Africa.
Rapid diagnostic tools have been shown to improve linkage of patients to care. In the context of infectious diseases, assessing the impact and cost-effectiveness of such tools at the population level, accounting for both direct and indirect effects, is key to informing adoption of these tools. Point-of-care (POC) CD4 testing has been shown to be highly effective in increasing the proportion of HIV positive patients who initiate ART. We assess the impact and cost-effectiveness of introducing POC CD4 testing at the population level in South Africa in a range of care contexts, using a dynamic compartmental model of HIV transmission, calibrated to the South African HIV epidemic. We performed a meta-analysis to quantify the differences between POC and laboratory CD4 testing on the proportion linking to care following CD4 testing. Cumulative infections averted and incremental cost-effectiveness ratios (ICERs) were estimated over one and three years. We estimated that POC CD4 testing introduced in the current South African care context can prevent 1.7% (95% CI: 0.4% - 4.3%) of new HIV infections over 1 year. In that context, POC CD4 testing was cost-effective 99.8% of the time after 1 year with a median estimated ICER of US$4,468/DALY averted. In healthcare contexts with expanded HIV testing and improved retention in care, POC CD4 testing only became cost-effective after 3 years. The results were similar when, in addition, ART was offered irrespective of CD4 count, and CD4 testing was used for clinical assessment. Our findings suggest that even if ART is expanded to all HIV positive individuals and HIV testing efforts are increased in the near future, POC CD4 testing is a cost-effective tool, even within a short time horizon. Our study also illustrates the importance of evaluating the potential impact of such diagnostic technologies at the population level, so that indirect benefits and costs can be incorporated into estimations of cost-effectiveness.


Resistance acquisition to MDM2 inhibitors.
Various experimental strategies aim to (re)activate p53 signalling in cancer cells. The most advanced clinically are small-molecule inhibitors of the autoregulatory interaction between p53 and MDM2 (murine double minute 2). Different MDM2 inhibitors are currently under investigation in clinical trials. As for other targeted anti-cancer therapy approaches, relatively rapid resistance acquisition may limit the clinical efficacy of MDM2 inhibitors. In particular, MDM2 inhibitors were shown to induce p53 mutations in experimental systems. In the present article, we summarize what is known about MDM2 inhibitors as anti-cancer drugs with a focus on the acquisition of resistance to these compounds.


An extraordinary gobioid fish fossil from Southern France.
The classification of gobioid fishes is still under discussion. Several lineages, including the Eleotridae and Butidae, remain difficult to characterize because synapomorphies are rare (Eleotridae) or have not yet been determined (Butidae). Moreover, the fossil record of these groups is scarce. Exceptionally well-preserved fish fossils with otoliths in situ from uppermost Oligocene sediments (≈23-24 Mio. y. ago) in Southern France provide the most in-depth description of a fossil gobioid to date. The species was initially described as Cottus aries Agassiz, then transferred to †Lepidocottus Sauvage, and subsequently assigned to Gobius. Based on a comparative analysis of meristic, osteological and otolith data, this species most likely is a member of the family Butidae. This discovery is important because it represents the first record of a fossil butid fish based on articulated skeletons from Europe. The Butidae and Eleotridae are currently distributed in W-Africa, Madagascar, Asia and Australia, but they do not appear in Europe and also not in the Mediterranean Sea. The new results indicate that several species of the Butidae thrived in Europe during the Oligocene and Early Miocene. Similar to the recent Butidae and Eleotridae, these fishes were adapted to a wide range of salinities and thrived in freshwater, brackish and marginal marine habitats. The fossil Butidae disappeared from Europe and the Mediterranean and Paratethys areas during the Early Miocene, due probably to their lack of competitiveness compared to other Gobioidei that radiated during this period of time. In addition, this study documents the great value of otoliths for gobioid systematics.


Comparison of the Asleep-Awake-Asleep Technique and Monitored Anesthesia Care During Awake Craniotomy: A Systematic Review and Meta-analysis.
Awake craniotomy (AC) is the preferred surgical option for intractable epilepsy and resection of tumors adjacent to or within eloquent cortical areas. Monitored anesthesia care (MAC) or an asleep-awake-asleep (SAS) technique is most widely used during AC. We used a random-effects modeled meta-analysis to synthesize the most recent evidence to determine whether MAC or SAS is safer and more effective for AC. We included randomized controlled trials and observational studies that explored the incidence of AC failure, duration of surgery, and hospital length of stay in adult patients undergoing AC. Eighteen studies were included in the final analysis. MAC was associated with a lower risk of AC failure when compared with SAS (global pooled proportion MAC vs. SAS 1% vs. 4%; odds ratio [ORs]: 0.28; 95% confidence interval [CI]: 0.11-0.71; P=0.007) and shorter surgical procedure time (global pooled mean MAC vs. SAS 224.44 vs. 327.94 min; mean difference, -48.76 min; 95% CI: -61.55 to -35.97; P<0.00001). SAS was associated with fewer intraoperative seizures (global pooled proportion MAC vs. SAS 10% vs. 4%; OR: 2.38; 95% CI: 1.05-5.39; P=0.04). There were no differences in intraoperative nausea and vomiting between the techniques (global pooled proportion MAC vs. SAS: 4% vs. 8%; OR: 0.86; 95% CI: 0.30-2.45; P=0.78). Length of stay was shorter in the MAC group (MAC vs. SAS 3.96 vs. 6.75 days; mean difference, -1.30; 95% CI: -2.69 to 0.10; P=0.07). In summary, MAC was associated with lower AC failure rates and shorter procedure time compared with SAS, whereas SAS was associated with a lower incidence of intraoperative seizures. However, there was a high risk of bias and other limitations in the studies included in this review, so the superiority of 1 technique over the other needs to be confirmed in larger randomized studies.


Beam quality degradation of a single-frequency Yb-doped photonic crystal fiber amplifier with low mode instability threshold power.
A current limit in power scaling of Yb-doped fiber amplifiers is the sudden onset of mode instabilities. We investigated this effect on a single-frequency Yb-doped photonic crystal fiber amplifier with a low mode instability threshold power. By measuring the overlap of the fiber output beam with the fundamental mode of an external cavity to be about 95%, we could exclude significant modal power transfer below a sharp power threshold. Furthermore, we directly measured the frequency resolved intensity noise spectra. No fluctuations in the overall output power were observed, but for the modal content different oscillation regimes were identified.


Faster is not surer--a comparison of C57BL/6J and 129S2/Sv mouse strains in the watermaze.
In recent years the use of genetic manipulations to investigate the molecular mechanisms underlying learning and memory has become a common approach. In a great many cases, the spatial learning ability of mutant mice has been assessed using the Morris watermaze task. The performance of these mice may, however, be strongly influenced by their genetic background and, therefore, the interpretation of their phenotype requires a preliminary characterization of the parental strains. The present study compared 129S2/Sv and C57/BL/6J inbred mouse strains, which have been widely used in deriving lines of genetically modified mice, on the hidden platform version of the watermaze task. During acquisition, the C57 mice displayed shorter escape latencies to find the platform than the 129S2s. Further analysis revealed, however, that the C57 mice also swam faster than the 129S2s. The analysis of path lengths was thus a more reliable measure of spatial learning, and revealed an equal level of performance in the two strains. This conclusion was confirmed during the two probe trials with both strains showing a similar spatial preference for the training site. These results suggest that the 129S2 substrain is no less proficient than the C57 substrain in terms of spatial learning in the watermaze, and also demonstrates the importance of not relying solely on escape latency as a measure of watermaze performance.


Mechanisms behind the superior effects of interval vs continuous training on glycaemic control in individuals with type 2 diabetes: a randomised controlled trial.
By use of a parallel and partly crossover randomised, controlled trial design we sought to elucidate the underlying mechanisms behind the advantageous effects of interval walking training (IWT) compared with continuous walking training (CWT) on glycaemic control in individuals with type 2 diabetes. We hypothesised that IWT, more than CWT, would improve insulin sensitivity including skeletal muscle insulin signalling, insulin secretion and disposition index (DI). By simple randomisation (sequentially numbered, opaque sealed envelopes), eligible individuals (diagnosed with type 2 diabetes, no exogenous insulin treatment) were allocated to three groups: a control group (CON, n = 8), an IWT group (n = 12) and an energy expenditure-matched CWT group (n = 12). Training groups were prescribed free-living training, five sessions per week (60 min/session). A three-stage hyperglycaemic clamp, including glucose isotope tracers and skeletal muscle biopsies, was performed before and after a 4 month intervention in a hospitalised setting. No blinding was performed. The improved glycaemic control, which was only seen in the IWT group, was consistent with IWT-induced increases in insulin sensitivity index (49.8 ± 14.6%; p < 0.001), peripheral glucose disposal (14.5 ± 4.9%; p < 0.05) and DI (66.2 ± 21.8%; p < 0.001), with no changes in the CWT or CON group. Moreover, only IWT improved insulin signalling in skeletal muscle via increased insulin-stimulated phosphorylation of AS160 (29.0 ± 10.8%; p < 0.05). No changes were seen in insulin secretion during hyperglycaemia alone, hyperglycaemia + glucagon-like peptide 1 infusion or arginine injection. IWT maintains insulin secretion and improves insulin sensitivity and DI, in contrast to energy expenditure-matched CWT. These results suggest that training with alternating intensity, and not just training volume and mean intensity, is a key determinant of changes in whole body glucose disposal in individuals with type 2 diabetes. ClinicalTrials (NCT01234155).


Successful treatment of an adult with Amanita phalloides-induced fulminant liver failure with molecular adsorbent recirculating system (MARS).
Despite significant advances in intensive care management of Amanita phalloides-induced fulminant liver failure (FLF), patients with this condition still have a high mortality rate in the absence of orthotopic liver transplantation. Molecular Adsorbent Recirculating System (MARS) is a new, cell-free, extracorporeal liver assistance method utilizing an albumin dialysate for the removal of albumin-bound toxins, and a highly effective depurative therapy in adults with wild mushroom-induced FLF. We report the case of a 39 year old woman with Amanita phalloides-induced FLF, admitted to our intensive care unit (ICU) and treated with MARS. Our patient had severe hepatic dysfunction: hepatic encephalopathy (grade II), ALT = 5022 (2475-10098) IU/L, bilirubin = 7.18 (4.8-10.1) mg/dL, prothrombin time (PT) = 90.4 (29.3-140.4) s. MARS sessions had an immediate impact on liver tests: statistically significant decrease in ammonia, ALT and PT. Hepatic encephalopathy was successfully reduced. The patient survived and the hepatic function completely recovered. MARS appears to be a safe and highly effective depurative therapy in adults with Amanita phalloides-induced FLF.


Bayesian color constancy.
The problem of color constancy may be solved if we can recover the physical properties of illuminants and surfaces from photosensor responses. We consider this problem within the framework of Bayesian decision theory. First, we model the relation among illuminants, surfaces, and photosensor responses. Second, we construct prior distributions that describe the probability that particular illuminants and surfaces exist in the world. Given a set of photosensor responses, we can then use Bayes's rule to compute the posterior distribution for the illuminants and the surfaces in the scene. There are two widely used methods for obtaining a single best estimate from a posterior distribution. These are maximum a posteriori (MAP) and minimum mean-square-error (MMSE) estimation. We argue that neither is appropriate for perception problems. We describe a new estimator, which we call the maximum local mass (MLM) estimate, that integrates local probability density. The new method uses an optimality criterion that is appropriate for perception tasks: It finds the most probable approximately correct answer. For the case of low observation noise, we provide an efficient approximation. We develop the MLM estimator for the color-constancy problem in which flat matte surfaces are uniformly illuminated. In simulations we show that the MLM method performs better than the MAP estimator and better than a number of standard color-constancy algorithms. We note conditions under which even the optimal estimator produces poor estimates: when the spectral properties of the surfaces in the scene are biased.


Why do women not deliver in health facilities: a qualitative study of the community perspectives in south central Ethiopia?
In Ethiopia most childbirth occurs at home and is not assisted by skilled birth attendants. On the other hand having a birth attendant with midwifery skills during child birth is one of the most important interventions in reducing maternal morbidity and mortality. The objective of this study was to make an in-depth assessment of reasons why mothers do not use health facilities for child delivery. Focus Group Discussions were used to gather information on use of health facilities for delivery in Butajira districts of South Central Ethiopia. The study was conducted from January to February 2012. Information was collected from four groups of women who had delivered in the past two years and four groups of men whose wives/partners have delivered in the same period. Data was coded and categorized using open code, qualitative data management software and analyzed based on thematic analysis. A total of eight FGD sessions, four with women and four with men groups were conducted involving 81 residents of the Butajira district. FGD participants answered that a large majority of women in the district gave birth at home. Two major themes, client related factors and facility/staff factors, emerged. Factors that emerged within major themes of client factors were decision making on place of delivery, reliance on Traditional Birth Attendants (TBAs), misconception about services provided at health facility, inability of family members to be present at time of labor and delivery, lack of privacy, traditional and/or spiritual factors, economic factors and accessibility to health care facilities. Within major themes of facility/staff factors subthemes that emerged were poor reception, refusal of admission, lack of privacy, information gap, poor competence and shortage of staff and materials at health facilities. Women in the study areas do not deliver in health facilities because of reasons that can be attributed to health care system and client related factors. These need to be addressed by considering the specific factors related to the health system and community perspectives.


Curcumin (diferuloylmethane) inhibits constitutive NF-kappaB activation, induces G1/S arrest, suppresses proliferation, and induces apoptosis in mantle cell lymphoma.
Human mantle cell lymphoma (MCL), an aggressive B cell non-Hodgkin's lymphoma, is characterized by the overexpression of cyclin D1 which plays an essential role in the survival and proliferation of MCL. Because of MCL's resistance to current chemotherapy, novel approaches are needed. Since MCL cells are known to overexpress NF-kappaB regulated gene products (including cyclin D1), we used curcumin, a pharmacologically safe agent, to target NF-kappaB in a variety of MCL cell lines. All four MCL cell lines examined had overexpression of cyclin D1, constitutive active NF-kappaB and IkappaB kinase and phosphorylated forms of IkappaBalpha and p65. This correlated with expression of TNF, IkappaBalpha, Bcl-2, Bcl-xl, COX-2 and IL-6, all regulated by NF-kappaB. On treatment of cells with curcumin, however, downregulated constitutive active NF-kappaB and inhibited the consitutively active IkappaBalpha kinase (IKK), and phosphorylation of IkappaBalpha and p65. Curcumin also inhibited constitutive activation of Akt, needed for IKK activation. Consequently, the expression of all NF-kappaB-regulated gene products, were downregulated by the polyphenol leading to the suppression of proliferation, cell cycle arrest at the G1/S phase of the cell cycle and induction of apoptosis as indicated by caspase activation, PARP cleavage, and annexin V staining. That NF-kappaB activation is directly linked to the proliferation of cells, is also indicated by the observation that peptide derived from the IKK/NEMO-binding domain and p65 suppressed the constitutive active NF-kappaB complex and inhibited the proliferation of MCL cells. Constitutive NF-kappaB activation was found to be due to TNF, as anti-TNF antibodies inhibited both NF-kappaB activation and proliferation of cells. Overall, our results indicate that curcumin inhibits the constitutive NF-kappaB and IKK leading to suppression of expression of NF-kappaB-regulated gene products that results in the suppression of proliferation, cell cycle arrest, and induction of apoptosis in MCL.


Realization of hybrid compressive imaging strategies.
The tendency of natural scenes to cluster around low frequencies is not only useful in image compression, it also can prove advantageous in novel infrared and hyperspectral image acquisition. In this paper, we exploit this signal model with two approaches to enhance the quality of compressive imaging as implemented in a single-pixel compressive camera and compare these results against purely random acquisition. We combine projection patterns that can efficiently extract the model-based information with subsequent random projections to form the hybrid pattern sets. With the first approach, we generate low-frequency patterns via a direct transform. As an alternative, we also used principal component analysis of an image library to identify the low-frequency components. We present the first (to the best of our knowledge) experimental validation of this hybrid signal model on real data. For both methods, we acquire comparable quality of reconstructions while acquiring only half the number of measurements needed by traditional random sequences. The optimal combination of hybrid patterns and the effects of noise on image reconstruction are also discussed.


Reducing financial barriers to emergency obstetric care: experience of cost-sharing mechanism in a district hospital in Burkina Faso.
To describe the implementation of a cost-sharing system for emergency obstetric care in an urban health district of Ouagadougou, Burkina Faso and analyse its results after 1 year of activity. Service availability and use, service quality, knowledge of the cost-sharing system in the community and financial viability of the system were measured before and after the system was implemented. Different sources of data were used: community survey, anthropological study, routine data from hospital files and registers and specific data collected on major obstetric interventions (MOI) in all the hospitals utilized by the district population. Direct costs of MOI were collected for each patient through an individual form and monitored during the year 2005. Rates of MOI for absolute maternal indications (AMI) were calculated for the period 2003-2005. The direct cost of a MOI was on average 136US$, including referral cost. Through the cost-sharing system this amount was shared between families (46US$), health centres (15US$), Ministry of Health (38US$) and local authority (37US$). The scheme was started in January 2005. The rate of cost recovery was 91.3% and the balance at the end of 2005 was slightly positive (4.7% of the total contribution). The number of emergency referrals by health centres increased from 84 in 2004 to 683 in 2005. MOI per 100 expected births increased from 1.95% in 2003 to 3.56% in 2005 and MOI for AMI increased from 0.75% to 1.42%. The dramatic increase in MOI suggests that the cost-sharing scheme decreased financial and geographical barriers to emergency obstetric care. Other positive effects on quality of care were documented but the sustainability of such a system remains uncertain in the dynamic context of Burkina Faso (decentralization).


LEDGF/DFS70, a major autoantigen of atopic dermatitis, is a component of keratohyalin granules.
Lens epithelium-derived growth factor/dense fine speckles 70 kDa protein (LEDGF/DFS70) is a transcriptional cofactor, a transcriptional activator, survival factor, and HIV-1 transporter. It is also a major autoantigen in patients with atopic dermatitis (AD), because autoantibodies to this protein are found in approximately 30% of AD patients. To better understand the role of autoantibodies and autoantigens in the pathogenesis of AD, we examined the distribution of LEDGF/DFS70 in the epidermis of normal human skin by light and electron microscopic immunocytochemistry. Increased amounts of LEDGF/DFS70 were located in the nuclei of cells in the basal layer, whereas the cytoplasm of cells in the granular layer stained for LEDGF/DFS70 by light microscopy. Using immunoelectron microscopy, we observed the accumulation of LEDGF/DFS70 in keratohyalin granules (KGs) in the cytoplasm of cells in the granular layer. In addition, Ig heavy chain-binding protein/glucose-regulated protein, 78-kDa (Bip/GRP78), a stress sensing protein in the endoplasmic reticulum, colocalized with LEDGF/DFS70 in the KGs. These results suggest that LEDGF/DFS70 is predominantly located in the nucleus of the basal epidermal cells and translocates into the cytoplasm during differentiation. Once in the cytoplasm, LEDGF/DFS70 accumulates in the KGs in the granular layer. Finally, LEDGF/DFS70, a "nuclear" autoantigen in AD, may play a functional role in the KGs.


Echocardiographic predictors of first onset of atrial fibrillation in dogs with myxomatous mitral valve disease.
Atrial fibrillation (AF) occurs in dogs with myxomatous mitral valve disease (MMVD) as a consequence of left atrial (LA) dilatation, and it affects survival and quality of life. To evaluate the usefulness of echocardiography in predicting the first occurrence of AF in dogs with MMVD. Forty-four client-owned dogs with MMVD, 22 dogs that developed AF, and 22 dogs that maintained sinus rhythm. Retrospective observational study. Medical databases were reviewed for dogs that developed AF during the year after diagnosis of MMVD (AF group). The last echocardiographic examination obtained while still in sinus rhythm was used to derive selected variables. For each dog with AF, a control dog matched for body weight, class of heart failure, and LA dimension was selected. Echocardiographic results including LA volumes and LA speckle tracking echocardiography (STE)-derived variables were measured. Among the tested echocardiographic variables, only LA diameter (P = .03) and left ventricular internal diameter in diastole (P = .03) differed significantly between groups, whereas body weight-indexed variables of cardiac dimension as well as LA volumes and volume-derived functional variables were not different. Among the STE-derived variables, peak atrial longitudinal strain (PALS) results differed significantly between the AF group (23.8% ± 8.6%) and the control group (30.5% ± 9.6%; P = .03). A value of PALS ≤28% predicted AF occurrence with sensitivity and specificity of 0.80 and 0.65, respectively. Absolute cardiac diameters and LA STE (in particular, PALS) are useful echocardiographic predictors for the development of AF in dogs with MMVD.


Interobserver and intraobserver reliability of the radiographic analysis of femoroacetabular impingement and dysplasia using computer-assisted measurements.
A comprehensive evaluation of hip radiographs in the young adult with hip pain has become increasingly complex and time consuming. The interobserver reliability of manually performed measurements of femoroacetabular impingement, including the alpha angle, has been questioned. Methods to improve the reliability of a radiographic evaluation may increase the clinical utility of these parameters. To determine the interobserver and intraobserver reliability of a computer-assisted radiographic analysis of the young adult hip in a clinically relevant setting. Cohort study (diagnosis); Level of evidence, 3. A reliability study of a comprehensive computer-assisted radiographic evaluation was performed, which included 25 radiographic parameters of proximal femoral morphology, acetabular morphology, hip osteoarthritis, and pelvic tilt/rotation. Anteroposterior pelvis and 45° Dunn lateral radiographs of 70 consecutive patients undergoing hip preservation surgery were included. Each radiograph was analyzed by 4 experienced hip surgeons. The reliability of continuous measurements was analyzed using intraclass correlation coefficients (ICCs), while categorical parameters were analyzed using κ values and percentages of agreement. The interobserver reliability of the parameters of proximal femoral morphology, acetabular morphology, and osteoarthritis was generally substantial to excellent. Parameters with lesser interobserver reliability included the alpha angle (ICC, 0.43), Tönnis osteoarthritis classification (κ = 0.22), and classification of pelvic tilt (using the coccyx or sacrococcygeal joint) (κ = 0.43 and 0.61, respectively). A computer-assisted analysis of young adult hip radiographs generally demonstrates substantial to excellent levels of interobserver reliability for most parameters. However, alpha angle measurements demonstrated only moderate interobserver reliability, despite excellent intraobserver reliability. Measurements of the joint space width appear to be significantly more reliable than the use of the Tönnis osteoarthritis classification in this population. The classification of pelvic tilt utilizing the coccyx or sacrococcygeal joint is only moderately reliable.


Parents' Views on the Best and Worst Reasons for Guideline-Consistent HPV Vaccination.
Background: Human papillomavirus (HPV) vaccination could prevent most HPV-associated cancers, but few U.S. adolescents are vaccinated according to guidelines. To inform efforts to counsel parents more effectively, we sought to quantify their views on the best and worst reasons for guideline-consistent HPV vaccination. We hypothesized that parents' views would differ according to their vaccination confidence.Methods: We developed a best-worst scaling experiment to evaluate 11 reasons healthcare providers commonly give for HPV vaccination. The instrument was administered in 2016 via a national online survey to 1,177 parents of adolescents. Parents completed 11 choice tasks of 5 reasons each, indicating the best and worst reason in each task. We used conditional logistic regression to rank reasons for the sample overall and by vaccination confidence (low/high).Results: Parents viewed cancer prevention as the best reason for HPV vaccination (P < 0.001). Other commonly endorsed reasons were preventing a common infection, having lasting benefits, or being a safe vaccine (all P < 0.001). Reasons viewed as worst were: It is a scientific breakthrough; I got it for my own child; and your child is due (all P < 0.001). Stratified analyses indicated small differences in how often parents with low versus high vaccination confidence endorsed messages (P < 0.001), but the two groups ranked reasons similarly overall.Conclusions: Parents prioritized cancer prevention as the best reason for guideline-consistent HPV vaccination. Several other common reasons, including having vaccinated one's own child, may warrant additional testing.Impact: Providers should emphasize cancer prevention when discussing HPV vaccination, as recommended by the Centers for Disease Control and Prevention, the President's Cancer Panel, and others. Cancer Epidemiol Biomarkers Prev; 27(7); 762-7. ©2018 AACR.


Gender differences in stage-adjusted bladder cancer survival.
Gender differences have been observed in the prognosis of patients with bladder cancer. It has also been suggested that these differences are caused by a worse stage distribution at diagnosis among women. The purpose of this study was to evaluate whether women with bladder cancer have a worse prognosis even after adjustment for disease stage at first presentation. Data on patients with bladder cancer diagnosed between 1973 and 1996 and registered by one of the nine population-based Surveillance, Epidemiology, and End Results (SEER) cancer registries in the United States (n = 80,305) were obtained from the National Cancer Institute public domain SEER*Stat 2.0 package. Similar data on patients with bladder cancer diagnosed between 1987 and 1994 and registered by two population-based registries in the Netherlands (n = 1722) were obtained through the Comprehensive Cancer Centers, Amsterdam and South. Survival rates adjusted for mortality owing to other causes (ie, relative survival) were calculated for men and women within each category of the American Joint Committee on Cancer (SEER data) and TNM (Netherlands data) stage groupings.Results. In the United States, the 5-year relative survival rate of male patients with bladder cancer was calculated to be 79.5% (95% confidence interval 79.0% to 80.0%). Among women, the 5-year relative survival rate was significantly worse: 73.1% (95% confidence interval 72.2% to 74.0%). The male versus female 5-year survival rate among stage groups I, II, III, and IV was 96.5% versus 93.7%, 65.5% versus 59.6%, 58.8% versus 49.6%, and 27.1% versus 15.2%, respectively. The (sparser) data from the Netherlands were less conclusive. Women with Stage II and Stage IV disease fared worse than men but the reverse seemed to be true in Stage I disease. Female patients with bladder cancer have a worse prognosis than male patients. It is unlikely that the difference can explained entirely by the more frequent diagnosis of higher stages at first presentation among women.


The influence of a salience distinction between bilateral cues on the latency of target-detection saccades.
The spatial cueing paradigm, with saccades to targets as the method of response, was used to investigate the influence of two simultaneously presented cues on the orienting of visual attention. Participants were presented with bilateral cues, one of which was perceptually salient (high luminance) relative to the other. They participated in one of three conditions: in the 'bright side likely' condition targets usually (p =.8) appeared near the more salient cue; in the 'dim side likely' condition targets usually (p =.8) appeared near the less salient cue; and in the 'neutral' condition the arrangement of the cues was uninformative with respect to target location. Brief SOAs (0, 50, 100 and 150 ms) were employed. Rapid reflexive orienting to the more salient stimulus was observed in the neutral condition: saccadic latencies were faster when the target appeared near the bright cue, and this was found even across the two shortest SOAs. However, this reflexive orienting was suppressed in both the bright side likely and dim side likely conditions: the advantage observed at the bright cue's location across the two shortest SOAs in the neutral condition was significantly attenuated in the two contingent conditions. Results point to rapid expectancy-based interference in the reflexive process of attention capture.


The increased costs of donation after cardiac death liver transplantation: caveat emptor.
To determine the effect of donation after cardiac death (DCD) livers on post-transplantation costs. DCD livers are increasingly being used to expand the donor pool despite higher complication rates. Although complications after liver transplantation have profound financial implications, the effect of DCD livers on post-transplantation costs has not been studied. We estimated direct medical care costs based on inpatient and outpatient hospital costs for 28 DCD and 198 donation after brain death (DBD) liver recipients. Organ acquisition and physician costs were excluded. Donor and recipient demographics were comparable for DCD and DBD transplants. One-year, post-transplantation costs were higher for DCD recipients (124.9% of DBD costs, P = 0.04). DCD costs remained higher (125.2% of DBD costs, P = 0.009) after adjusting for recipient characteristics. Furthermore, DCD post-transplantation costs were 30% higher than DBD costs after adjusting for pre-transplantation costs (P = 0.02). Biliary complications (DCD 58% vs. DBD 21%; P < 0.001) and, specifically, ischemic cholangiopathy (DCD 44% vs. DBD 1.6%; P < 0.001) occurred more frequently after DCD transplantation. Moreover, DCD recipients underwent retransplantation more often (DCD 21% vs. DBD 7.1%, P = 0.02). One-year costs were increased for recipients with ischemic cholangiopathy or retransplantation by 53% (P = 0.01) and 107% (P < 0.001), respectively. However, DCD costs continued to be higher when retransplanted patients were excluded (120% of DBD costs, P = 0.02). Higher rates of graft failure and biliary complications translate into markedly increased direct medical care costs for DCD recipients. These important financial implications should be considered in decisions regarding the use of DCD livers.


Effect of local anesthetic concentration, dose and volume on the duration of single-injection ultrasound-guided axillary brachial plexus block with mepivacaine: a randomized controlled trial.
In what way volume, concentration and dose affect block duration is controversial. The purpose of the present study is to investigate the effect of dose, volume and concentration of mepivacaine on the duration of sensory and motor blockade in ultrasound-guided single shot axillary brachial plexus blockade. In this parallel group randomized trial conducted in the Sint Maartenskliniek Nijmegen, 45 adult patients undergoing minor orthopaedic forearm, wrist or hand surgery were randomized to 3 groups. Group A: 20 mL mepivacaine 1.5 %, Group B: 30 mL mepivacaine 1 % and Group C: 30 mL mepivacaine 1.5 %. Randomization was computer-generated, with allocation concealment by opaque sequentially numbered sealed envelopes. Patients and observers were blinded to group allocation. duration of sensory block. Forty-five patients were randomized, four patients were excluded and replaced, and 15 patients in each group were included in the analysis. Mean (95 % CI) sensory and motor block duration was 256 (230-282) and 254 (226-282) minutes in Group A, 226 (209-243) and 220 (200-240) minutes in Group B and 270 (249-291) and 264 (244-284) minutes in Group C. Duration of sensory and motor block duration differed significantly between groups (p = 0.012 and p = 0.016 respectively). Post-hoc analysis showed a significantly reduced sensory and motor block duration in Group B when compared to Group C of 44 min. No local anesthetic systemic toxicity was reported. When using mepivacaine for axillary brachial plexus block, a higher dose and concentration was associated with a longer duration of sensory and motor blockade, but not a higher volume. The Netherlands National Trial Register NTR3648 . Registered October 3, 2012.


Olfactory dysfunction in humans with deficient guanine nucleotide-binding protein.
The guanine nucleotide-binding stimulatory protein (Gs) couples hormone-receptor interaction to the activation of adenylate cyclase and the generation of cyclic AMP. Studies using frog neuroepithelium indicate that the sense of smell is mediated by a Gs-adenylate cyclase system, and this prompted us to test olfaction in the only known model of Gs deficiency in the animal kingdom, Gs-deficient (type 1a) pseudohypoparathyroidism (PHP), which occurs in humans. Such patients are resistant to the cAMP-mediated actions of several hormones. (Although Henkin has reported disturbances in the sense of smell in six patients with PHP, currently available biochemical measurements such as the cAMP response to parathyroid hormone (PTH) and determination of Gs activity were not reported and olfactory testing was limited.) In the present study, we found that all Gs-deficient patients had impaired olfaction when compared with PHP patients who had normal Gs activity (type 1b PHP, in which patients are resistant only to the action of PTH in the kidney). This is the first evidence of human olfactory impairment which can be related to Gs deficiency and suggests that Gs-deficient PHP patients may be resistant to cAMP-mediated actions in other non-endocrine systems.


MicroRNA expression in pre-treatment plasma of patients with benign breast diseases and breast cancer.
MicroRNAs (miRs) are small RNA molecules, influencing messenger RNA (mRNA) expression and translation, and are readily detectable in blood. Some have been reported as potential breast cancer biomarkers. This study aimed to identify and validate miRs indicative of breast cancer. Based on the discovery and literature, 18 potentially informative miRs were quantified in the validation cohort. Irrespective of patient and tumour characteristics, hsa-miR-652-5p was significantly upregulated in the malignant compared to benign patients (1.26 fold, P = 0.005) and therefore validated as potential biomarker. In the validation cohort literature-based hsa-let-7b levels were higher in malignant patients as well (1.53 fold, P = 0.011). Two miRs differentiated benign wildtype from benign BRCA1 mutation carriers and an additional 8 miRs differentiated metastastic (n = 8) from non-metastatic (n = 41) cases in the validation cohort. Pre-treatment plasma samples were collected of patients with benign breast disease and breast cancer and divided over a discovery (n = 31) and validation (n = 84) cohort. From the discovery cohort miRs differentially expressed between benign and malignant cases were identified using a 2,000-miR microarray. Literature-based miRs differentiating benign from malignant disease were added. Using RT-qPCR, their expression was investigated in a validation cohort consisting of pre-treatment benign, malignant and metastatic samples. Additionally, benign and malignant cases were compared to benign and malignant cases of BRCA1-mutation carriers. Plasma microRNA levels differed between patients with and without breast cancer, between benign disease from wildtype and BRCA1-mutation carriers and between breast cancer with and without metastases. Hsa-miR-652-5p was validated as a potential biomarker for breast cancer.


Zinc toxicosis in a dog secondary to prolonged zinc oxide ingestion.
Zinc toxicosis is commonly associated with ingestion of metallic zinc objects. This report documents an uncommon presentation of zinc toxicosis, secondary to prolonged ingestion of a zinc oxide cream. A 5.6 kg 6-year-old ovariohysterectomised female Poodle cross presented as a transfer to an emergency practice for severe anaemia, pigmenturia, weakness, and inappetence. She had a history of vomiting and nine days of diarrhoea. Amongst other supportive treatments, a zinc oxide cream had been applied to her hind end due to severe diarrhoea scalding, and in hindsight, the owners realised she had ingested large quantities of this cream. She developed a severe Heinz body haemolytic anaemia, along with spherocytosis, left-shift neutrophilia, prolonged activated partial thromboplastin time, and mildly elevated blood urea nitrogen. The serum zinc concentration was markedly elevated. She was treated supportively and made a full recovery. This case illustrates the importance of a thorough medical history. Zinc toxicosis can have a good prognosis when diagnosed and treated promptly.


The dominance of haptics over audition in controlling wrist velocity during striking movements.
Skilled interactions with sounding objects, such as drumming, rely on resolving the uncertainty in the acoustical and tactual feedback signals generated by vibrating objects. Uncertainty may arise from mis-estimation of the objects' geometry-independent mechanical properties, such as surface stiffness. How multisensory information feeds back into the fine-tuning of sound-generating actions remains unexplored. Participants (percussionists, non-percussion musicians, or non-musicians) held a stylus and learned to control their wrist velocity while repeatedly striking a virtual sounding object whose surface stiffness was under computer control. Sensory feedback was manipulated by perturbing the surface stiffness specified by audition and haptics in a congruent or incongruent manner. The compensatory changes in striking velocity were measured as the motor effects of the sensory perturbations, and sensory dominance was quantified by the asymmetry of congruency effects across audition and haptics. A pronounced dominance of haptics over audition suggested a superior utility of somatosensation developed through long-term experience with object exploration. Large interindividual differences in the motor effects of haptic perturbation potentially arose from a differential reliance on the type of tactual prediction error for which participants tend to compensate: vibrotactile force versus object deformation. Musical experience did not have much of an effect beyond a slightly greater reliance on object deformation in mallet percussionists. The bias toward haptics in the presence of crossmodal perturbations was greater when participants appeared to rely on object deformation feedback, suggesting a weaker association between haptically sensed object deformation and the acoustical structure of concomitant sound during everyday experience of actions upon objects.


Intrahousehold disparities in women and men's experiences of water insecurity and emotional distress in urban Bolivia.
This study is one of the first to examine the links connecting water insecurity, gender, and emotional distress. The article presents quantitative and qualitative analyses of interview data collected from randomly selected pairs of male and female household heads (n=48) living under the same household-level conditions of water insecurity., The results provide partial confirmation of past findings that women are more likely than men to be burdened with everyday water responsibilities. However, there were no significant differences between men's and women's experiences in household water emergencies (i.e., water shortages and last-ditch attempts to buy water) and reports on some measures of emotional distress (i.e., worry, annoyance, and anger with family members). The results suggest that intrahousehold gender disparities may be mitigated in times of severe water scarcity. The discussion raises questions about the comparability of men's and women's expressions of emotional distress.


CIP2A Promotes T-Cell Activation and Immune Response to Listeria monocytogenes Infection.
The oncoprotein Cancerous Inhibitor of Protein Phosphatase 2A (CIP2A) is overexpressed in most malignancies and is an obvious candidate target protein for future cancer therapies. However, the physiological importance of CIP2A-mediated PP2A inhibition is largely unknown. As PP2A regulates immune responses, we investigated the role of CIP2A in normal immune system development and during immune response in vivo. We show that CIP2A-deficient mice (CIP2AHOZ) present a normal immune system development and function in unchallenged conditions. However when challenged with Listeria monocytogenes, CIP2AHOZ mice display an impaired adaptive immune response that is combined with decreased frequency of both CD4+ T-cells and CD8+ effector T-cells. Importantly, the cell autonomous effect of CIP2A deficiency for T-cell activation was confirmed. Induction of CIP2A expression during T-cell activation was dependent on Zap70 activity. Thus, we reveal CIP2A as a hitherto unrecognized mediator of T-cell activation during adaptive immune response. These results also reveal CIP2AHOZ as a possible novel mouse model for studying the role of PP2A activity in immune regulation. On the other hand, the results also indicate that CIP2A targeting cancer therapies would not cause serious immunological side-effects.


Shadow enhancers foster robustness of Drosophila gastrulation.
Critical developmental control genes sometimes contain "shadow" enhancers that can be located in remote positions, including the introns of neighboring genes [1]. They nonetheless produce patterns of gene expression that are the same as or similar to those produced by more proximal primary enhancers. It was suggested that shadow enhancers help foster robustness in gene expression in response to environmental or genetic perturbations [2, 3]. We critically tested this hypothesis by employing a combination of bacterial artificial chromosome (BAC) recombineering and quantitative confocal imaging methods [2, 4]. Evidence is presented that the snail gene is regulated by a distal shadow enhancer located within a neighboring locus. Removal of the proximal primary enhancer does not significantly perturb snail function, including the repression of neurogenic genes and formation of the ventral furrow during gastrulation at normal temperatures. However, at elevated temperatures, there is sporadic loss of snail expression and coincident disruptions in gastrulation. Similar defects are observed at normal temperatures upon reductions in the levels of Dorsal, a key activator of snail expression (reviewed in [5]). These results suggest that shadow enhancers represent a novel mechanism of canalization whereby complex developmental processes "bring about one definite end-result regardless of minor variations in conditions" [6].


Examining Burnout in Interprofessional Intensive Care Unit Clinicians Using Qualitative Analysis.
Health care professionals working in intensive care units report a high degree of burnout, but this topic has not been extensively studied from an interdisciplinary perspective. To characterize experiences of burnout among members of interprofessional intensive care unit teams and identify possible contributing factors. This qualitative study involved interviews of registered nurses, respiratory therapists, physicians, pharmacists, and a personal care assistant working in multiple intensive care units of a single academic medical center to assess work stressors. Team composition was a factor in burnout, particularly when nonphysician team members felt that their opinions were not valued despite the institution's emphasis on a multidisciplinary team-based model of care. This was especially true when roles were not well defined at the outset of a code situation. Members of nearly all disciplines stated that there was not enough time in a day to complete all the required tasks. Multiple factors contribute to work-related stress and burnout across different professions in the intensive care unit. Improved communication and increased receptivity to diverse opinions among members of the multidisciplinary team may help reduce stress.


Operative Strategies to Minimize Complications Following Resection of Pituitary Macroadenomas.
Introduction We sought to identify factors associated with increased length of stay (LOS) and morbidity in patients undergoing resection of pituitary macroadenomas. Methods We reviewed records of 203 consecutive patients who underwent endoscopic endonasal resection of a pituitary macroadenoma (mean age = 55.7 [16-88]) years, volume = 11.3 (1.0-134.3) cm3. Complete resection was possible in 60/29.6% patients. Mean follow-up was 575 days. Multivariate logistic regression was performed using MATLAB. Results Mean LOS was 4.67 (1-66) days and was associated with CSF leak (p = 0.025), lumbar drain placement (p = 0.041; n = 8/3.9% intraoperative, n = 20/9.9% postoperative), and any infection (p = 0.066). Age, diabetes insipidus (n = 17/8.37%), and syndrome of inappropriate antidiuretic hormone secretion (n = 12/5.9%) were not associated with increased LOS (p > 0.2). Postoperative CSF leak in the hospital (n = 21/10.3%) was associated with intraoperative CSF leak (p = 0.002; n = 82/40.4%) and complete resection (p = 0.012). There was no significant association (p > 0.1) between postoperative CSF leak in the hospital following surgery and the use of a fat graft (n = 61/30.1%), nasoseptal flap (155/76.4%), or perioperative lumbar drain placement (n = 8/3.94%). Conclusion Complete resection is associated with increased risk of CSF leak and LOS. Operative strategies including placement of fat graft, nasoseptal flap, or intraoperative lumbar drain placement may have limited value in reducing the risk of postoperative CSF leak.


Unexpected costs of high working memory capacity following directed forgetting and contextual change manipulations.
Greater working memory capacity is usually associated with greater ability to maintain information in the face of interruptions. In two experiments, we found that some types of interruptions actually lead to greater forgetting among high-span people than among low-span people. Specifically, an instruction designed to change mental context resulted in significant forgetting for high-span people but minimal forgetting among the low-span people. Intentional forgetting instructions also resulted in greater forgetting among higher working memory capacity participants than among lower working memory capacity participants. A candidate explanation called the intensified context shift hypothesis is proposed which suggests that high-span people are more context dependent than low-span people.


The patient exit interview as an assessment of physician-delivered smoking intervention: a validation study.
In evaluating the efficacy of physician-delivered counseling interventions for health behavior changes such as smoking cessation, a major challenge is determining the degree to which interventions are implemented by physicians. The Patient Exit Interview (PEI; J. Ockene et al., 1991) is a brief measure of a patient's perception of the content and quantity of smoking cessation intervention received from his or her physician. One hundred eight current smokers seen in a primary care clinic completed a PEI following their physician visit. Participants were 45% male, 95% Caucasian, with a mean age of 42 years and an average of 22 years of smoking. The PEI correlated well with a criterion measure of an audiotape assessment of the physician-patient interaction (r = .67, p < .001). When discrepancy occurred, in general it was due to patients' over-reporting of intervention as compared with the criterion measure. Implications and limitations of these findings are discussed.


Biologics, colchicine, corticosteroids, immunosuppressants and interferon-alpha for Neuro-Behçet's Syndrome.
Neuro-Behçet Syndrome (NBS) is a severe chronic inflammatory vascular disease involving the Central Nervous System (CNS), and it is an invalidating condition with disability and a huge impact on quality of life. Recommendations on treatments for NBS include the use of disease-modifying therapies in general, although they are not supported by a systematic review of the evidence. To assess the benefit and harms of available treatments for NBS, including biologics, colchicine, corticosteroids, immunosuppressants and interferon-alpha. We searched the following databases up to 30 September 2014: Trials Specialised Register of The Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group, CENTRAL, MEDLINE, EMBASE, CINAHL, LILACS, ORPHANET, Clinicaltrials.gov and World Health Organization (WHO) International Clinical Trials Registry Portal. Randomised controlled trials (RCTs), controlled clinical trials (CCTs), prospective and retrospective controlled cohort studies were eligible to assess the benefit. Patients over 13 years of age with a diagnosis of NBS. For assessment of harms, open-label extension (OLE), case-control studies, population-based registries, case-series and case-reports were additionally planned to be evaluated. Selection of studies, data extraction and assessment of risk of bias were planned to be carried out independently by two review authors. Standard methodological procedures expected by The Cochrane Collaboration were followed. We planned to perform standard pair-wise meta-analyses for RCTs, and meta-analyses based on the adjusted estimates using the inverse-variance weighted average method for non-randomised studies (NRSs). We planned to present the main results of the review in a 'Summary of Findings' table using the GRADE approach. No RCTs, CCTs or controlled cohort studies on the benefit of the treatments for NBS met the inclusion criteria of the review. Only one potentially eligible study was identified, but it did not report sufficient details on the patient characteristics. The author of this study did not provide additional data on request, and therefore it was excluded. Hence, no studies were included in the present review. Since no studies were included in the assessment of benefit, no further search was performed in order to collect data on harms. There is no evidence to support or refute the benefit of biologics, colchicine, corticosteroids, immunosuppressants and interferon-alpha for the treatment of patients with NBS. Thus, well-designed multicentre RCTs are needed in order to inform and guide clinical practice.


PTK7/CCK-4 is a novel regulator of planar cell polarity in vertebrates.
In addition to the apical-basal polarity pathway operating in epithelial cells, a planar cell polarity (PCP) pathway establishes polarity within the plane of epithelial tissues and is conserved from Drosophila to mammals. In Drosophila, a 'core' group of PCP genes including frizzled (fz), flamingo/starry night, dishevelled (dsh), Van Gogh/strabismus and prickle, function to regulate wing hair, bristle and ommatidial polarity. In vertebrates, the PCP pathway regulates convergent extension movements and neural tube closure, as well as the orientation of stereociliary bundles of sensory hair cells in the inner ear. Here we show that a mutation in the mouse protein tyrosine kinase 7 (PTK7) gene, which encodes an evolutionarily conserved transmembrane protein with tyrosine kinase homology, disrupts neural tube closure and stereociliary bundle orientation, and shows genetic interactions with a mutation in the mouse Van Gogh homologue vangl2. We also show that PTK7 is dynamically localized during hair cell polarization, and that the Xenopus homologue of PTK7 is required for neural convergent extension and neural tube closure. These results identify PTK7 as a novel regulator of PCP in vertebrates.